Stable crystalline salt of (R)-3-fluorophenyl-3,4,5-trifluorobenzylcarbamic acid 1-azabicyclo [2.2.2]oct-3-yl ester

ABSTRACT

The present invention refers to a stable crystalline salt of (R)-3-fluorophenyl-3,4,5-trifluorobenzylcarbamic acid 1-azabicyclo[2.2.2]oct-3-yl ester and its use as medicament, in particular for the treatment of urinary incontinence or other diseases involving genitourinary disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is filed under the provisions of 35 U.S.C. §371 andclaims the priority of International Patent Application No.PCT/EP2008/010012 filed on 26 Nov. 2008 entitled “Stable CrystallineSalt of (R)-3-Fluorophenyl-3,4,5-Trifluorobenzylcarbamic Acid1-Azabicyclo[2.2.2]Oct-3-yl Ester” in the name of Juan Lorenzo CatenaRuiz, et al., which claims priority of European Patent Application No.07384038.1 filed on 28 Nov. 2007, both of which are hereby incorporatedby reference herein in their entirety.

FIELD OF THE INVENTION

The present invention relates to a stable crystalline salt of(R)-3-fluorophenyl-3,4,5-trifluorobenzylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester and to pharmaceutical formulations ofthis salt, in particular for medical use including treatment of urinaryincontinence urge or other diseases involving genitourinary disorders.

BACKGROUND OF THE INVENTION

WO0200652 discloses compound I((R)-3-fluorophenyl-3,4,5-trifluorobenzylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester) which has the following formula (I)

Compound I is also disclosed in WO2004000840. On the other hand,compound I is exemplified as hydrochloride salt in WO2003053966 as anintermediate in the synthesis of other compounds. However, this acidaddition salt known from the prior art had the disadvantage that itsphysicochemical stability was poor. Upon storage or formulation of saidknown salt, progressive decomposition and concomitantly an increase inthe amount and number of impurities was observed. Obviously, thisproblem is further aggravated under demanding environmental conditionssuch as light, heat, humidity or acidity.

SUMMARY OF THE INVENTION

It has been particularly difficult to find stable, crystalline forms of(R)-3-fluorophenyl-3,4,5-trifluorobenzylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester. The hydrochloride salt of compound Ihas the disadvantage of being highly hygroscopic, and when purified, theinitial white foam quickly becomes a sticky gum due to its humidityuptake. Thus, there remains a need for a salt of(R)-3-fluorophenyl-3,4,5-trifluorobenzylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester that forms a crystalline solid thathas a desirable morphology, be stable in the presence of water and underconditions of a high relative humidity (above 85%) and can readily beprepared on a large scale.

It has now been found that the above mentioned problem can be solvedwith the D-tartrate salt of compound I. The D-tartrate salt is morestable than the hydrochloride salt at room, enhanced temperature and atrelative high humidity and in aqueous media. In addition, thisD-tartrate salt in crystalline form has also been found to be stable,highly soluble in water and easy to handle or process.

Thus, a first aspect of the invention relates to a D-tartrate salt ofcompound I, ((R)-3-fluorophenyl-3,4,5-trifluorobenzylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester) of structural formula (II):

possessing a stoichiometry of substantially 1:1 of compound I toD-tartaric acid, and in the form of crystalline polymorph I, which ischaracterized by an X-Ray powder diffractogram pattern with peaks at °2θas shown in FIG. 1.

A second aspect of the invention relates to a pharmaceutical compositioncomprising a D-tartrate salt of compound I as described above, with atleast one pharmaceutically acceptable carrier or excipient.

A third aspect of the invention relates to a D-tartrate salt of compoundI as described above for use as a medicament.

A further aspect of the invention relates to the use of a D-tartratesalt of compound I as described above in the preparation of a medicamentfor the treatment of a disease or condition involving genitourinarydisorders, in particular for the treatment of urinary incontinence, andmore particularly for the treatment of overactive bladder.

A further aspect of the invention relates to a method for the treatmentof a disease or condition involving genitourinary disorders, inparticular for the treatment of urinary incontinence, and moreparticularly for the treatment of overactive bladder, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a D-tartrate salt of compound I as described above.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Shows an X-ray powder diffractogram (XRPD) of a crystallineD-tartrate salt of compound I, polymorph I (obtained using copper Kαradiation) prepared in Example 2.

FIG. 2: Shows an X-ray powder diffractogram (XRPD) of a crystallineD-tartrate salt of compound I, polymorph II (obtained using copper Kαradiation) prepared in Example 3.

FIG. 3: Shows a DSC of a crystalline D-tartrate salt of compound I,prepared in Example 2.

FIG. 4: Shows a DSC of a crystalline D-tartrate salt of compound I,prepared in Example 3.

FIG. 5: Shows a DSC of a crystalline D-tartrate salt of compound I,prepared in Example 4.

FIG. 6: Shows a DSC of a crystalline D-tartrate salt of compound I,prepared in Example 5.

FIG. 7A shows the isotherms derived from the data shown in FIG. 7B byrepresenting the equilibrium mass change values at each relativehumidity step. Isotherms are divided into two components: sorption forincreasing humidity steps and desorption for decreasing humidity steps.

FIG. 7B shows the vapor sorption kinetic obtained by exposing theproduct to a series of step changes in relative humidity and monitoringthe mass change as a function of time. The darker line represents themass change of the product as a function of time and the lighter linewith squares represents the relative humidity as a function of time.

FIG. 8: Shows a FT-Raman of a crystalline D-tartrate salt of compound I,prepared in Example 1.

FIG. 9: Shows a FT-Raman of a crystalline D-tartrate salt of compound I,prepared in Example 3.

FIG. 10: Shows a FT-Raman of a crystalline D-tartrate salt of compoundI, prepared in Example 4.

FIG. 11A: Shows FT-Raman differences between the different polymorphs(FIGS. 8, 9 and 10) for 1-3500 cm⁻¹.

FIG. 11B: Shows FT-Raman differences between the different polymorphs(FIGS. 8, 9 and 10) for 2850-3150 cm⁻¹.

FIG. 11C: Shows FT-Raman differences between the different polymorphs(FIGS. 8, 9 and 10) for 760-810 cm⁻¹.

Further details for the figures are revealed in the Examples below.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a D-tartrate salt of compound I.D-tartrate provides optimal properties for formulation due to itsstability, and it has the structural formula (II):

In order to be considered as a candidate for further development as apharmaceutical, a compound must not only possess desirable biologicalproperties, but also physical properties that permit its use in themanufacture of a pharmaceutical composition. In particular, the compoundshould form a stable, preferably crystalline, solid that can be readilymanufactured and formulated.

Salt formation studies provide a means of altering the physicochemicaland resultant biological characteristics of a drug without modifying itschemical structure. A salt form can have a dramatic influence on theproperties of the drug. The selection of a suitable salt is partiallydictated by yield, rate and quantity of the crystalline structure. Inaddition, hygroscopicity, stability, solubility and the process profileof the salt form are important considerations. Solubility of a salt formcan affect its suitability for use as a drug. Where aqueous solubilityis low, i.e. less than 10 mg/ml, the dissolution rate at in vivoadministration can be rate limiting in the absorption process leading topoor bioavailability. Hygroscopicity is also an importantcharacteristic. Compounds having low hygroscopicity tend to have betterstability and easier processing. Stability at low and high relativehumidity is desirable in a product to be used or sold in a widediversity of environments.

The inventors have found that it is difficult to obtain a suitable saltof compound I for pharmaceutical formulation. The present invention hasovercome these problems with the D-tartrate salt disclosed herein, whichis crystalline, is relatively non-hygroscopic, and generally has betterphysical properties than other salts of the compound. Also, it has beenfound that the final content of impurities may be significantly reducedby precipitation of the D-tartrate salt of compound I as describedherein.

To select the most suitable salt of compound I and minimize theundesirable hygroscopic properties of the hydrochloride, several acidswere tested. The free base of compound I was dissolved in hot ethanol,and then acid solution in hot ethanol was added. The mixture was thenstirred and heated for 30 min. After cooling to room temperature, thesolvent was removed by evaporation. Acids tested included acetic,L-ascorbic, benzenesulphonic, (RS)-10-camphorsulfonic,(S)-10-camphorsulfonic, citric, embonic, fumaric, DL-lactic, L-lactic,maleic, D-malic L-malic, DL-malic, malonic, mandelic, D-mandelic,L-mandelic, methanesulphonic, orotic, oxalic, propionic, sorbic,succinic, DL-tartaric, L-tartaric and D-tartaric. The results concerningthe salts obtained were as indicated in Table 1.

TABLE 1 Acid Aspect of the salt Acetic Hygroscopic white foamL(+)-Ascorbic White foam Benzenesulphonic Oil (RS)-10-CamphorsulfonicHygroscopic pink foam (S)-10-Camphorsulfonic Oil Citric Oil EmbonicYellow solid Fumaric (0.5 eq) White foam Fumaric White foam HydrochloricHygroscopic white foam DL-Lactic Oil L-Lactic Oil Maleic Oil D-Malic(0.5 eq) Hygroscopic red foam DL-Malic (0.5 eq) Hygroscopic red foamD-Malic Hygroscopic red foam L-Malic (0.5 eq) Oil L-Malic Oil DL-MalicHygroscopic red foam Malonic Oil Mandelic White foam (S)-Mandelic Oil(R)-Mandelic Oil Methanesulphonic Oil Orotic Acid too insoluble inethanol Oxalic Hygroscopic white foam Propionic Hygroscopic white foamSorbic Oil Succinic Hygroscopic white foam DL-Tartaric Adding MTBEprecipitated a white solid L-Tartaric (0.5 eq) White foam D-Tartaric(0.5 eq) White solid crystal precipitated in EtOH. L-Tartaric White foamD-Tartaric White solid crystal precipitated in EtOH.

As indicated in Table 1, most of the acids tested yielded oils orhygroscopic foams, whereas salt obtained with D-tartaric acid was theonly one to yield a non-hygroscopic solid crystal under theseconditions.

D-tartaric acid is a dicarboxylic acid and thus it may form bothhydrogentartarate and tartrate salts. The invention refers to both asalt in which the molar ratio of compound I to tartaric acid is about1:1 (i.e., a hydrogentartarate) and a salt in which the molar ratio ofcompound I to tartaric acid is about 2:1 (i.e., a tartrate), as well asmixed salts, with for example an alkali metal or ammonium cation. Thecrystalline polymorphs (i.e. Forms I, II, III, and IV) of D-tartrate ofcompound I discussed below are hydrogentartarate salts, i.e., the molarratio of compound I to tartaric acid is about 1:1.

Salts of the present invention can be crystalline and may exist as morethan one polymorph. Hydrates as well as anhydrous forms of the salt arealso encompassed by the invention. In particular the anhydrous form ofthe D-tartrate salt of compound I is preferred. In an embodiment of theinvention, the salt is a substantially anhydrous crystalline salt.

D-tartaric acid salts may be formed by contacting stoichiometric amountsof the acid with compound I free base. Alternatively, the acid may beused in excess, usually no more than 1.25 equivalents. Preferably thebase and/or the acid are in solution, more preferably both are insolution.

Broadly speaking, the crystalline salts of the invention may be preparedby mixing a solution of either reactant in solvent, i.e. a suitablesingle solvent or a suitable mixture of solvents, preferably at roomtemperature or at elevated temperature, or by adding a solution ofeither reactant to a solid form of the other reactant and withsubsequent precipitation of the crystalline compound I salt. The term “asolvent” as used herein include both a single solvent or a mixture ofdifferent solvents. It is understood that the solvent may comprise wateras the case may be, e.g. about 0-20% water. The term suitable solvent asused herein in relation to the preparation of the D-tartrate salt andthe recrystallization defines any lower alkanol, water or ketone solventin which the compound I is soluble and includes primary, secondary andtertiary alcohols and the corresponding ketones of from 1 to 6 carbonatoms. Suitable lower alkanol solvents include, but are not limited to,methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol,2-methyl-1-propanol, 1,1-dimethyl-ethanol and cyclohexanol.

Improved yield may be obtained by evaporation of some or all of thesolvent or by crystallization at elevated temperatures followed bycontrolled cooling, preferably in stages. Careful control ofprecipitation temperature and seeding may be used to improve thereproducibility of the production process and the particle sizedistribution and form of the product. Particularly good yields have beenobtained using EtOH as solvent. Conveniently(R)-3-Fluorophenyl-3,4,5-trifluorobenzylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester and one equivalent of D-tartaric acidare dissolved in hot EtOH. Seeding with a small quantity of previouslyprepared crystals may help initiate crystallization.

The present invention also provides four crystalline polymorphic formsof D-tartrate of compound I (hereinafter referred to as Forms I, II,III, and IV, respectively).

The pharmaceutical composition of the present invention may compriseabout 20, 30, 40, 50, 60, 70, 80, 90, 95, 96, 97, 98, 99, 99.1, 99.2,99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9 or 100% by weight of Form I,II, III, or IV of D-tartrate of compound I, based upon 100% total weightof D-tartrate of compound I in the pharmaceutical composition (or thetotal weight of crystalline D-tartrate of compound I in thepharmaceutical composition).

Crystalline polymorph Form I of D-tartrate of compound I is stable atroom temperature. Form I is physically stable at room temperature but itis enantiotropically related with Form II, this means that at roomtemperature Form I (lower melting polymorph) is the more stable one andat higher temperatures the higher melting polymorph (Form II) is themore stable one. According to Differential Scanning calorimetry (DSC),Form I has a double endotherm at about 139° C. and at about 145° C. (seeFIG. 3).

Form I may be prepared from the free base of compound I as follows. Thefree base of compound I and D-tartaric acid are dissolved in hotethanol. The solution is then slowly cooled (e.g., for 3 hours orlonger) to yield Form I of D-tartrate of compound I. The crystals ofForm I may be recovered by any method known in the art.

Form I can also be prepared by preparing a slurry containing Form II,Form III or Form IV, or a mixture thereof, with EtOH at roomtemperature.

Any crystal prepared by the aforementioned methods may be recovered bytechniques known to those skilled in the art, such as, for example,filtration.

Crystalline polymorph Form II of D-tartrate of compound I was obtainedunder controlled temperature conditions and according to DSC has anendotherm at about 149° C. (see FIG. 4).

Crystalline polymorph Form III of D-tartrate of compound I was obtainedby equilibration in Water and according to DSC has an broad endotherm atabout 110° C. (see FIG. 5).

Crystalline polymorph Form IV of D-tartrate of compound I was obtainedby equilibration in hot Ethanol (60° C.) and according to DSC has anendotherm at about 162° C. (see FIG. 6).

As used herein, by expressions like “crystalline form of a specific saltof compound I characterized by the X-Ray powder diffractogram shown inFIG. (1)” is meant the crystalline form of salt of compound I inquestion having an X-ray powder diffractogram substantially similar toFIG. (1), i.e. exhibiting an X-ray powder diffraction patternsubstantially as exemplified in that Figure and measured undercomparable conditions as described herein or by any comparable method.Generally, all data herein are understood to be approximate and subjectto normal measurement error depending e.g. on the apparatus used andother parameters influencing peak positions and peak intensities.

The reaction of (R)-3-Quinuclidinol with carbonyldiimidazole (CDI) indichloromethane, at 0° C. during 4 h, afford the correspondingimidazolide carbamate (intermediate 2).

Intermediate 1 was obtained by imine formation between3,4,5-trifluorobenzaldehyde and 3-fluoroaniline (in a Dean-Stark system)and later reduction with sodium borohydride in ethanol.

The key coupling reaction was carried out by deprotonation of the amine(intermediate 1) with hexyl lithium at −10° C. and subsequent additionof imidazolide (intermediate 2), in THF, at −10° C., stirring it during2 h.

Finally, D-tartrate of compound I was obtained by crystallization in hotethanol adding 1 equivalent of D-tartaric acid to the compound I.

An object of the invention is a pharmaceutical composition comprisingthe active pharmaceutical ingredient (D-tartrate of compound I) ormixture of the active pharmaceutical ingredient with other activepharmaceutical ingredients and/or pharmaceutically acceptable carriersor excipients.

Such pharmaceutical composition can be administered orally, in the formof powders, granulates, tablets, capsules, lozenges, multiparticulates,lyophilised forms, solutions or suspensions, transdermal or buccalpatches, emulsions or microemulsions, for immediate-, ormodified-release applications (sustained-, delayed- or pulsed-releaseapplications). Such pharmaceutical composition, as described above, maybe administered by direct intake or as soluble, dispersible,orodispersible, chewable, effervescent or bioadhesive dosage forms, orthrough the skin.

Powders and granulates may be obtained by direct mix o successive mix oftheir components or by dry or wet granulation, aqueous or organic.Powders and granulates may contain excipients such as diluents, binders,disintegrants, wetting agents, glidants, lubricants, plastificants,absorbent or adsorbent agents, immediate- or modified-release polymers,sweetening or flavouring agents, colouring matter or dyes agents, orpreservatives and may be dosified as monodose or multidosepharmaceutical forms.

Tablets cited above may be obtained from powders, granulates, othertablets or lozenges or any combination thereof. These tablets may be anyconventional, multilayer, effervescent, dispersible, soluble,orodispersible, gastro-resistant, modified release, bioadhesive,chewable, buccal or matricial dosage forms. These tablets may also becoated with one or more functional layers in order to protect the activepharmaceutical ingredient or modify its release. Any layer may containthe active pharmaceutical ingredient, alone or with one or moremodified-release polymers. Tablets described above may containexcipients such as diluents, binders, disintegrants, wetting agents,glidants, lubricants, plastificants, absorbent or adsorbent agents,immediate- or modified-release polymers, sweetening or flavouringagents, colouring matter or dyes agents, or preservatives.

Capsules cited above may be manufactured from gelatin, HPMC, cellulosicor polysaccharide derivates, flour cereals or a combination thereof, andmay be soft or hard capsules. Capsules may contain powders, granulates,multiparticulate pharmaceutical forms, tablets, lozenges, liquids orsemisolids, or a combination thereof. These capsules may also be coatedwith one or more functional layers in order to protect the activepharmaceutical ingredient or modify its release. Any layer may containthe active pharmaceutical ingredient, alone or with one or moremodified-release polymers. Capsules described above may containexcipients such as diluents, binders, disintegrants, wetting agents,glidants, lubricants, plastificants, absorbent or adsorbent agents,immediate- or modified-release polymers, sweetening or flavouringagents, colouring matter or dyes agents, or preservatives.

Multiparticulate pharmaceutical forms may be administered under amonodose or multidose way. These pharmaceutical forms may beadministered as capsules, tablets, sachets or strips, suspensions,solutions, vials, flasks or bottles or any other device. Suchmultiparticulate pharmaceutical forms may be used for immediate ormodified-release applications and obtained from an inert or active corecontaining the active pharmaceutical ingredient. Cores may be coated byone or more functional layers in order to protect or modify the releaseof the active pharmaceutical ingredient. This ingredient may be includedin one or more layers, alone or with one or more modified-releasepolymers. Additional layers, including protecting agents ormodified-release polymers may be included in other external layer nextto the layer containing the active pharmaceutical ingredient. Suchmultiparticulate pharmaceutical forms may contain excipients suchdiluents, binders, disintegrants, wetting agents, glidants, lubricants,plastificants, absorbent or adsorbent agents, immediate- ormodified-release polymers, sweetening or flavouring agents, colouringmatter or dyes agents, or preservatives.

The liquid and semi-solid pharmaceutical forms, as solutions,suspensions, gels, emulsions, micro-emulsions and others, incorporatethe active ingredient, in a soluble form, disperse or in amultiparticular form, and adequate excipients. They can be dosed inmonodose or multidose form, being able to be of extemporaneouspreparation. It can contain excipients such as emulsifiers, solubilityenhancers, dispersants, humectants, co-emulsifiers, emollients,viscosity increasing agents, vehicles, preservatives, pH adjustmentagents, flavouring agents or sweeteners. These components can be liquidsof aqueous, lipidic or organic nature.

The active pharmaceutical ingredient may be released via the skin, orany suitable external surface, including mucosal membranes, such asthose found inside the mouth. Transdermal or buccal patches mayincorporate the drug into the device and be included in a matrix, in anadhesive or in a reservoir. Formulates may incorporate wetting agents,immediate- or modified-release polymers, enhancers, emulsifiers,dispersants, co-emulsifiers, solubility enhancers, adhesives,humectants, emollients, viscosity increasing agents, vehicles,preservatives or pH adjustment agents. These components can besemisolids or liquids, of aqueous, lipidic or organic nature. Matrix maybe solid or semisolid in one or more layers. Patches include a permeablemembrane on one side and also some form of adhesive to maintain thepatch in place on the patient's skin, with the membrane in contact withthe skin so that the medication can diffuse out of the patch reservoirand into and through the skin. The outer side of the patch is formed ofan impermeable layer of material, and the membrane side and the outerside are joined around the perimeter of the patch, forming a reservoirfor the medication and carrier between the two layers.

EXAMPLES Analytical Methods

¹H-NMR and ¹³C-NMR spectra was recorded at 400 MHz and 100.61 MHzrespectively on a Bruker ARX 400 instrument. Dimethyl sulfoxide (99.8%D) was used as solvent, and tetramethylsilane (TMS) was used as internalreference standard.

The purity of D-tartrate of compound I was determined by HPLC/MS using aGemini 5 u C18 110A, 50×4.6 mm column at 25° C. The mobile phase was 70%of solution A (0.025 M orthophosphoric acid at pH 3.0-3.1 withtriethylamine) and 30% of solution B (Acetonitrile/methanol (9:1)) at aflow rate of 1.4 ml/minute. Run time 20 min. Detection was performedusing a UV detector at 200 nm. D-tartrate of compound I showed aretention time of approximately 6.5 min.

The enantiomeric excess of compound I was determined by using aQuirabiotic V-2 column, 25×0.46 cm L, at 25° C. The mobile phase 0.1%(w/v) trifluoroacetic acid in methanol adjusted to pH about 6.5 withammonium hydroxide at a flow rate of 0.5 ml/min, run time 25 min.Detection was performed using a UV detector at 230 nm. D-tartrate ofcompound I had a retention time of approximately 16 min, and itsenantiomer had a retention time of approximately 17 min.

The Melting points were measured using Differential Scanning calorimetry(DSC). The equipment was a Perkin Elmer DSC 7 or a Perkin Elmer Pyris 1with various crucibles (gold, alumina, open, closed, microhole), heatingrate variable and range variable.

X-Ray powder diffractograms were measured on a Philips X'Pert PW 3040 orPhilips PW 1710 using Cu kα radiation. The samples were measured inreflection mode in the 2θ-range 2-50°

FT-Raman Spectroscopy was registered on a Bruker RFS100 equipment.Nd:YAG 1064 nm excitation, 100 mW laser power, Ge-detector, 64 scans,range 25-3500 cm⁻¹, 2 cm⁻¹ resolution.

TG-FTIR: Netzsch Thermo-Microbalance TG 209 with Bruker FT-IRSpectrometer Vector 22. Al-crucible (open or with Microhole); N₂atmosphere, heating rate 10° C. min⁻¹, range 25-250° C.

Dynamic Vapour Sorption (DVS). The equipment was a Surface MeasurementSystems Ltd. DVS-1 Water vapour sorption analyser. The sample was placedon a quartz or platinum holder on top of a microbalance, and the samplewas allowed to equilibrate at 50% r.h. before starting a pre-definedhumidity program.

Specific rotation measurements were performed using a polarimeter fromSchmidt+Haensch, model Polartronic-E (series number 27586), equippedwith a thermostatic bath from Techne, model TE-8J.

Synthesis Example 1 Synthesis of(R)-3-fluorophenyl-3,4,5-trifluorobenzylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester (compound I) Intermediate 2(R)-imidazole-1-Carboxylic acid 1-azabicyclo[2.2.2]oct-3-yl ester

To a suspension of 1.86 Kg of (R)-3-quinuclidinol in 30 L ofdichloromethane, 2.92 Kg of DCI were added at 0° C. The solution wasstirred during 3 h under inert atmosphere. Then, 23 L of water wereadded and extracted. The organic layer was dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theobtained white solid was crystallized with isopropyl acetate(IPAC)-heptane to give 24.1 Kg of the title compound.

IR (KBr, cm⁻¹): 1746;

¹H-NMR: 1.33-1.43 (m, 1H); 1.47-1.57 (m, 1H); 1.58-1.70 (m, 1H);1.75-1.87 (m, 1H); 2.07-2.12 (m, 1H); 2.56-2.90 (m, 5H); 3.18 (ddd,J=14.5, J=8, J=2, 1H); 4.95-5.00 (m, 1H); 7.07 (s, 1H); 7.61 (s, 1H);8.29 (s, 1H).

¹³C-NMR: 18.9; 23.7; 24.9; 45.7; 46.6; 54.1; 75.7; 117.3; 130.1; 137.1;147.9.

Intermediate 1 (3-Fluorophenyl)-(3,4,5-trifluorobenzyl)amine

In a 300 L reactor fitted with a Dean-Stark funnel and refluxingcondenser, toluene (63 L), 3,4,5-trifluorobenzaldehyde (2.1 Kg) and3-fluoroaniline (1.33 Kg) were refluxed (112° C.) during 10 h.

After cooling, the resulting solution was concentrated to give the imineas an oil in a quantitative yield (3.2 Kg). Then ethanol (35 L) andsodium borohydride (0.5 Kg) was added. The resulting suspension wasstirred 3 h, Then, 42 L of water were added, the ethanol was distilledoff and the aqueous layer extracted with dichloromethane (2×40 L). Theorganic layer was dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure giving 2.72 kg of the titlecompound as an yellow oil.

1H-NMR: 4.29 (s, 2H); 4.33 (br., 1H), 6.28 (dtd, J=11, J=2.5; J=1, 1H),6.40 (ddd, J=8.5; J=2, J=1, 1H), 6.46 (tdt, J=8.5; J=2.5, J=1); 7.24(dd, J=8; J=7, 2H); 7.14 (tdd, J=8; J=6.5, J=1).

¹³C-NMR: 47.1; 99.9 (d, J=25.5); 104.8 (d, J=21); 109.1 (d, J=2); 111.0(d, J=10.5); 111.0 (d, J=21.5); 149.4 (dd, J=11, J=1); 136.0 (tdd, J=6,J=4, J=2); 139.0 (dt, J=248, J=5); 151.6 (ddd, J=248, J=10, J=4); 164.3(d, J=241).

Compound I (R)-3-Fluorophenyl-3,4,5-trifluorobenzylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester

To a solution of 2.72 Kg of intermediate (1) in 17 L of THF, cooled at−10° C., were added slowly (2 h), under inert atmosphere, 3 Kg of hexylLithium (33% in hexanes) and the resulting mixture was stirred for 1 hat −10° C. Then at −10° C. 2.41 Kg of intermediate 2 in 23 L of THF wereslowly added (75 min). The resulting mixture was stirred for 2 h andallowed to rise room temperature, then water was added and the solutionwas extracted with methyl tertbuthylether. The organic phase was driedover anhydrous sodium sulfate and the solvent was removed under reducedpressure giving 3.6 kg of the title compound as an orange oil.

Example 2 Synthesis of (R)-3-Fluorophenyl-3,4,5-trifluorobenzylcarbamicacid 1-azabicyclo[2.2.2]oct-3-yl ester (compound I) D-tartrate salt

To a solution of 3 Kg of(R)-3-fluorophenyl-3,4,5-trifluorobenzylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester (compound I) in ethanol (3 L) at 60°C., 1.1 Kg D-tartaric acid in 30 L of ethanol, warmed at 60° C. wereadded and the resulting mixture stirred 1 h and then cooled to belowroom temperature and kept at this temperature for 1 hour. Theprecipitate is filtered off and the filter cake is washed with ethanol(8 L). The filter cake is sucked free of most of the solvent, and theproduct is dried at 45° during 16 h. Yielding 3.5 kg of the titlecompound as a white crystalline solid.

¹H-NMR: 1.45-1.49 (m, 2H) 1.65-1.75 (m, 2H), 2.05 (m, 1H); 2.87-3.01 (m,3H); 3.07-3.11 (m, 1H); 3.08-3.11 (d, J=14, 1H); 3.39-3.45 (ddd, J=12,J=8, J=2, 1H); 4.00 (s, 2H); 4.83-4.89 (m, 1H); 4.84-4.89 (d, J=16.5,1H); 4.93-4.97 (d, J=16.5, 1H); 7.05 (td, J=8.5; J=2, 1H); 7.21 (dd,J=8; J=1.5, 1H); 7.24 (dd, J=8.5; J=7, 2H), 7.33-7.38 (m, 2H).

¹³C-NMR: 17.1; 20.4; 24.0; 44.5; 45.1; 51.6; 52.7; 69.5; 72.1; 111.8 (d,J=19.5); 113.4 (d, J=20.5); 114.1 (d, J=22); 122.6; 130.3 (d, J=9);135.1; 137.8 (dt, J=246, J=16); 142.6 (d, J=9); 150.2 (ddd, J=246,J=9.5, J=3.5); 154.0; 161.9 (d, J=242); 174.7

Elemental Analysis. Calculated for C₂₅H₂₆F₄N₂O₈: C, 53.77; H, 4.69; N,5.02. Found: C, 53.63; H, 4.73; N, 5.01

An XRPD pattern for the crystals prepared is shown in FIG. 1.

Specific rotation was determined. 1.00 g of substance was diluted withmethanol in a 100 mL volumetric flask. α (c=1, MeOH) c=g/100 mL. Themeasured specific rotation was −35.2°.

On the other hand, the equilibrium solubility of the D-tartrate saltwith several solvents was measured at 25° C. and was found to be(measured as the free base) as indicated in Table 2.

TABLE 2 Solvent Solubility (mg/ml) Methanol 258.5 Ethanol 10 Isopropylalcohol 1.5 Dichloromethane 2.2 Hexane 0.3 n-Octanol 0.5 Water 250.8 0.1Hydrochloric acid 366.6 0.1N sodium hydroxide 0.09

Evaluation of Hygroscopicity: No significant mass gain or mass loss wasobserved at 93% RH or below conditions. A significant water additionissue was observed at 97% RH, but no hygroscopicity issues related tostandard atmospheric conditions are expected as shown in Table 3.

TABLE 3 HYGROSCOPICITY STUDY (KF initial = 0.9692%) Time (h) 12% RH 22%RH 33% RH 43% RH 53% RH 64% RH 75% RH 85% RH 93% RH 97% RH 4 −0.26 −0.16−0.25 −0.38 −0.19 −0.08 −0.08 0.16 0.16 1.51 8 −0.20 −0.26 −0.24 −0.32−0.21 −0.07 0.02 0.13 0.03 1.06 14 −0.30 −0.25 −0.21 −0.21 −0.16 −0.070.01 0.22 0.24 4.36 48 −0.04 −0.21 −0.19 −0.25 −0.17 0.02 0.06 0.26 0.447.86 72 −0.28 −0.24 −0.23 −0.31 −0.16 −0.07 0.01 0.14 0.41 10.88 96−0.30 −0.26 −0.17 −0.30 −0.19 −0.07 −0.06 0.07 0.40 13.77 144 −0.33−0.18 −0.30 −0.40 −0.17 0.15 −0.08 0.24 0.43 23.58 168 −0.32 −0.28 −0.39−0.34 −0.16 0.15 −0.05 0.18 0.39 23.62 192 −0.27 −0.21 −0.11 −0.19 −0.200.20 0.00 0.15 0.38 23.06 216 −0.29 −0.19 −0.15 −0.25 −0.14 0.25 0.010.23 0.43 22.13 240 −0.08 −0.11 −0.18 −0.18 0.00 0.59 0.29 0.59 0.8119.88

Example 3 Preparation of Form II of D-Tartrate of Compound I

Form I (Example I) was treated as follows in DSC: Closed pan (STGF),0.0295 g, 25 to 143.5° C., 2° C. min⁻¹, scan down to 130° C., holdisotherm for 15 minutes, cool to 25° C.

Example 4 Preparation of Form III of Compound I D-Tartrate

0.49 g of form I were suspended in 1 mL of water and then shaken at 20°C. during 10 minutes (until dissolution), after 2 h the sample wasthickened.

Example 5 Preparation of Form IV of Compound I D-Tartrate

0.522 g of form I were suspended in 1 mL of EtOH abs. and then shaken at60° C., After 1 day the suspension disappeared and a new whitecrystalline crust was formed above the solvent sticking on the containerwall.

The invention claimed is:
 1. A D-tartrate salt of compound I((R)-3-fluorophenyl-3,4,5-trifluorobenzylcarbamic acid1-azabicyclo[2.2.2]oct-3-yl ester) of structural formula:

possessing a stoichiometry of substantially 1:1 of compound I toD-tartaric acid, and in the form of crystalline polymorph I, which ischaracterized by an X-Ray powder diffractogram pattern with peaks at °2θ as shown in FIG.
 1. 2. The salt of claim 1, which is a substantiallyanhydrous crystalline salt.
 3. A pharmaceutical composition comprising asalt of claim 1 with at least one pharmaceutically acceptable carrier orexcipient.
 4. A salt according to claim 1 for use as a medicament.
 5. Apharmaceutical composition comprising a salt of claim 2 with at leastone pharmaceutically acceptable carrier or excipient.
 6. A saltaccording to claim 2 for use as a medicament.